![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
,2
* Department of Nutrition, Harvard School of Public Health, Boston, MA 02115 and the
Centro Centroamericano de Población, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica
2To whom correspondence should be addressed. E-mail: hcampos{at}hsph.harvard.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
KEY WORDS: • arachidonic acid • fatty acids • myocardial infarction • adipose tissue • risk factors
Arachidonic acid (AA)3 is a long-chain (n-6) fatty acid (FA) [20:4(n-6)] that results from the elongation and desaturation of linoleic acid [18:2(n-6)] or directly from the diet (1). Because AA is a precursor of proinflammatory and proaggregatory eicosanoids, it was hypothesized that diets rich in (n-6) FAs, specifically linoleic acid, can have detrimental health effects (2,3). However, intervention studies showed that AA does not accumulate in human tissues after major increases in dietary linoleic acid (4–7). These observations question the potential adverse health effects that may occur with dietary linoleic acid. The conversion of linoleic acid to AA could be modified by the (n-3) FA content of the diet, e.g., 
-linolenic acid [18:3(n-3)] because these 2 FA families compete for the same desaturases in the metabolic pathways (8). Thus, increasing dietary (n-3) FAs could reduce the formation of AA and its effect on coronary heart disease (CHD) (8). Most epidemiologic studies show a cardiovascular protective effect of (n-6) PUFA, (9–12) but studies on the direct effect of AA on CHD are scarce (13,14). Interestingly, the variant form of the 5-lipoxygenase gene that codes for the enzyme involved in the first step of AA conversion to eicosanoids increases atherosclerosis, particularly among consumers of diets high in AA (15). We tested the hypothesis that increased AA in adipose tissue is associated with increased risk of nonfatal acute myocardial infarction (MI), and if so, whether this association is related to linoleic or -linolenic acid in adipose tissue and in the diet.
|
SUBJECTS AND METHODS |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
One free-living control subject for each case, matched for age (±5 y), sex, and area of residence (county), was randomly selected using the information available at the National Census and Statistics Bureau of Costa Rica. Participation was 97% for cases and 90% for controls. All subjects gave informed consent on documents approved by the Human Subjects Committee of the Harvard School of Public Health and the University of Costa Rica.
Data collection. All cases and controls were visited at their homes for data collection. Anthropometric measurements and biological specimens were collected in the morning at the subject’s home, after an overnight fast (16,17). A subcutaneous adipose tissue biopsy was collected from the upper buttock and stored at –80°C until analysis (19). Adipose tissue was sampled an average of 3 wk after acute nonfatal MI. Adipose tissue was selected because it was established that it has a very long half-life (1–2 y) (6) and it is not affected by acute events (20). Sociodemographic characteristics, smoking, socioeconomic status, and medical history data were collected during an interview using a questionnaire. Dietary intake was collected using a FFQ that was developed and validated specifically to assess FA intake among the Costa Rican population (19,21). Although the main exposure is adipose tissue AA, dietary information from the FFQ is useful to understand the characteristics of the study population and to investigate whether nutrients not measured in adipose tissue could confound the association between adipose tissue AA and MI. Self-reported diabetes and hypertension were validated as previously described (17).
Fatty acid analysis. Fatty acids from adipose tissue were quantified by GLC (19). Peak retention times and area percentages of total FA were identified using known standards (Nu-Chek-Prep), and analyzed with the Agilent Technologies ChemStation A.08.03 software. Duplicate samples (n = 12), indistinguishable from others, were analyzed throughout the study. The between assay CV for linoleic and AA were 5.5 and 11.2%, respectively.
Statistical analysis.
All data were analyzed with the Statistical Analysis Systems software (SAS Institute). Of the 1061 subjects that were recruited, 466 cases and 466 controls with complete data on adipose tissue FA and potential confounders were used in the final analysis. The significance of differences in crude means and frequencies for health characteristics and potential confounders were assessed by paired t tests and McNemar’s test. Spearman correlation coefficients were calculated to show the association between FAs in diet and adipose tissue and within FAs in adipose tissue. Odds ratios (OR) and 95% CI for adipose tissue AA quintiles were estimated from multiple conditional logistic regression models. Confounders were selected among potential risk factors for MI if they were associated with AA among the controls (exposure) and had an effect on the AA-MI association, or if they were biologically relevant. Variables included in the final models were waist-to-hip ratio (quintiles), household income (quintiles), history of diabetes (yes/no), history of hypertension (yes/no), smoking status (never, past, <10 cigarettes/d, 10–20 cigarettes/d, >20 cigarettes/d), adipose tissue linoleic (quintiles), adipose tissue -linolenic (quintiles), adipose tissue total trans (quintiles), saturated fat intake (quintiles), alcohol intake (never, past intake, current intake divided in tertiles), and total energy intake (quintiles). Other potential confounders examined but not included in the final models were BMI, physical activity, history of hypercholesterolemia, multivitamin use, aspirin use, nonsteroidal anti-inflammatory drugs, intake of vitamin E, vitamin C, folate, fiber, dietary cholesterol, and total fat. In adipose tissue, we examined oleic acid, 
-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid as potential confounders, in addition to those included in the final model (linoleic acid, -linolenic, and total trans). Tests for trend were performed across quintiles, using the median value for each of the quintiles modeled as a continuous variable. We tested for the statistical significance of interactions between adipose tissue AA and other variables using the likelihood ratio test.
|
RESULTS |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
-linolenic acid [18:3(n-6)] the first product of desaturation, were significantly lower in cases than in controls. In contrast, FAs that result from increasing carbon chain length and desaturation [20:3(n-6), 20:4(n-6), and 22:4(n-6)] were significantly higher in cases than in controls.
|
|
-linolenic [20:3(n-6)], an immediate precursor of AA, were highly correlated (r = 0.60); thus, statistical adjustment was not possible. The OR for the highest quintile of dihomo--linolenic acid was 2.85 (95% CI = 1.37, 5.94), although most likely the effect of dihomo--linolenic on MI is due to AA.
|
-linolenic acid, which is strongly protective in this population and is present in many oils and foods that contain linoleic acid (16). |
DISCUSSION |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
- linolenic and linoleic acid) the risk of MI in this population (16,22,23). The validity of our findings is enhanced by the population-based, case-control design with high participation (97 and 90%, respectively), the standardized study procedures for inclusion of cases of a first MI, the large number of case subjects, and the assessment of exposure using adipose tissue, a stable marker of FAs after acute MI because of its slow turnover (6). Results in the Costa Rican population are supported by those of a recent study in Israel (13) in which the risk of MI was 97% higher among subjects with the highest adipose tissue AA (3rd tertile) compared with the lowest, after adjusting for confounders. It is noteworthy that these findings are similar even with the large diet differences between Israel and Costa Rica. For example, polyunsaturated vegetable oils are used extensively in Israel, and this high level of intake is reflected in a very high proportion (25%) of linoleic acid in adipose tissue (13). In contrast, the use of palm oil is common in the Costa Rican population, where linoleic acid represents only 13% of total FAs in adipose tissue. Other studies did not detect significant associations between adipose tissue AA and MI (24–26). Yet, case subjects from these studies tended to have higher AA adipose tissue levels than controls (24–26).
A few studies examined the association between AA in blood and MI (24,27,28). Consistent with our observation, AA in erythrocytes was higher in cases of cardiac arrest compared with controls (28). In contrast, other studies showed that AA in platelets or plasma was significantly lower among cases than in controls (14,24). Interestingly, discrepant results were observed even in the same study in which an association with MI was found with lower platelet AA, but not with lower adipose tissue (24), or with lower AA in serum phospholipids, but not with serum triglyceride or cholesterol esters (27). There are several possible explanations for these conflicting results. Fatty acid biomarkers in blood (e.g., plasma, RBC) and adipose tissue can result in different outcomes because they could reflect tissue-specific properties. In muscle, phospholipid AA is positively related to insulin sensitivity (29). However, Phinney et al. (30,31) reported altered AA homeostasis in obese Zucker rats, in which a metabolic shift of AA was observed from phospholipids to cholesterol esters in liver. Thus, although obese rats had lower proportions of AA in liver phospholipids, they had higher proportions in cholesterol esters. Furthermore, the absolute amount of AA in carcass fat was 5 times higher in obese than in lean rats (30,31). In our study, we analyzed AA in RBC and adipose tissue in a subset of 200 controls. Consistent with data from animal studies, we found that the correlation between AA in RBC (mostly phospholipids) and adipose tissue AA was very low (r = 0.11), but when restricting the analysis to obese subjects (BMI 
30), the correlation becomes negative (r = –0.45 in men and r = –0.24 in women) (unpublished data). Thus, it is possible that individual tissues reflect different metabolic pools of AA, and our findings in adipose tissue do not necessarily reflect potential associations with other tissues.
The association between adipose tissue AA and MI could be related to the role of AA as a precursor of eicosanoids (2,3). Although adipose tissue FA concentrations do not necessarily represent flux through the tissues, increased AA in adipose tissue could reflect increased mobilization of AA in other important tissues such as the arterial intima. The association between AA and MI could also be mediated by insulin sensitivity in adipose tissue or elsewhere. Altered distribution of AA in tissues was correlated with alterations in lipogenesis and insulin action (8,30,32,33). Also, increased adipose tissue AA is associated with BMI (8,30,32,33). In fact, in our study, we found a relatively high correlation between AA and BMI, particularly among men (r = 0.40). AA is an activator of the peroxisome proliferator-activated receptors that modulate insulin sensitivity (34), and it is more adipogenic than (n-3) FAs (35). Still, we cannot rule out that the effects of AA on MI could reflect lower (n-3) FAs or a correlation with increased trans FAs, both predictors of MI in our population (16,22). In our analysis, we adjusted for these factors; however, although it is unlikely, residual confounding remains a possibility.
Our data suggest that at the current intake of our population, dietary linoleic acid intake does not result in increased AA in adipose tissue because there was no association between adipose tissue AA and dietary or adipose linoleic acid, a finding consistent with a study in another population (13). These observations are supported by feeding studies showing either no change (4,5) or even lower (7) AA levels in tissues after subjects consumed diets rich in linoleic acid. In the classic study by Dayton et al. (6) in which 393 subjects consumed an experimental diet rich in unsaturated FA for 5 y, linoleic acid in serum was substantially higher among subjects in the experimental diet compared with those in the control diet, but no differences in AA levels were observed even after 3 y of follow-up (6). These studies clearly show that AA is likely to be subjected to tight metabolic control, and its dietary precursor linoleic acid does not increase its concentration in tissues. Thus, it is unlikely that a diet high in linoleic acid increases the risk of MI because of its conversion to AA; in fact, both epidemiologic studies and clinical trials show that linoleic acid is protective.
In conclusion, we found that increased adipose tissue AA is associated with MI. Our results suggest that this association is independent of dietary and adipose tissue linoleic acid, as well as of other (n-6) and (n-3) FAs. Human studies that investigate how AA levels are regulated in vivo are warranted. Identification of these pathways could lead to novel targets to lower the risk of coronary disease.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
3 AA, arachidonic acid; CHD, coronary heart disease; FA, fatty acid; MI, myocardial infarction.
Manuscript received 3 July 2004. Initial review completed 21 July 2004. Revision accepted 17 August 2004.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
1. Zhou, L. & Nilsson, A. (2001) Sources of eicosanoid precursor fatty acid pools in tissues. J. Lipid Res. 42:1521-1542.
2. Simopoulos, A. P. (1999) Essential fatty acids in health and chronic disease. Am. J. Clin. Nutr. 70:560S-569S.
3. James, M. J., Gibson, R. A. & Cleland, L. G. (2000) Dietary polyunsaturated fatty acids and inflammatory mediator production. Am. J. Clin. Nutr. 71:343S-348S.
4. Sacks, F. M., Stampfer, M. J., Munoz, A., McManus, K., Canessa, M. & Kass, E. H. (1987) Effect of linoleic and oleic acids on blood pressure, blood viscosity, and erythrocyte cation transport. J. Am. Coll. Nutr. 6:179-185.[Abstract]
5. Mantzioris, E., James, M., Gibson, R. & Cleland, L. (1995) Differences exist in the relationships between dietary linoleic and alpha-linolenic acids and their respective long-chain metabolites. Am. J. Clin. Nutr. 61:320-324.
6. Dayton, S., Hashimoto, S., Dixon, W. & Pearce, M. L. (1966) Composition of lipids in human serum and adipose tissue during prolonged feeding of a diet high in unsaturated fat. J. Lipid Res. 7:103-111.[Abstract]
7. Raatz, S. K., Bibus, D., Thomas, W. & Kris-Etherton, P. (2001) Total fat intake modifies plasma fatty acid composition in humans. J. Nutr. 131:231-234.
8. Vessby, B., Gustafsson, I.-B., Tengblad, S., Boberg, M. & Andersson, A. (2002) Desaturation and elongation of fatty acids and insulin action. Ann. N.Y. Acad. Sci. 967:183-195.
9. Shekelle, R. B., Shryock, A. M., Paul, O., Lepper, M., Stamler, J., Liu, S. & Raynor, W. J., Jr (1981) Diet, serum cholesterol, and death from coronary heart disease. The Western Electric study. N. Engl. J. Med. 304:65-70.[Abstract]
10. Kushi, L. H., Lew, R. A., Stare, F. J., Ellison, C. R., el Lozy, M., Bourke, G., Daly, L., Graham, I., Hickey, N. & Mulcahy, R., et al (1985) Diet and 20-year mortality from coronary heart disease. The Ireland-Boston Diet-Heart Study. N. Engl. J. Med. 312:811-818.[Abstract]
11. Dolecek, T. A. (1992) Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial. Proc. Soc. Exp. Biol. Med. 200:177-182.[Abstract]
12. Hu, F. B., Stampfer, M. J., Manson, J. E., Rimm, E., Colditz, G. A., Rosner, B. A., Hennekens, C. H. & Willett, W. C. (1997) Dietary fat intake and the risk of coronary heart disease in women. N. Engl. J. Med. 337:1491-1499.
13. Kark, J. D., Kaufmann, N. A., Binka, F., Goldberger, N. & Berry, E. M. (2003) Adipose tissue n-6 fatty acids and acute myocardial infarction in a population consuming a diet high in polyunsaturated fatty acids. Am. J. Clin. Nutr. 77:796-802.
14. Wang, L., Folsom, A. R. & Eckfeldt, J. H. (2003) Plasma fatty acid composition and incidence of coronary heart disease in middle aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Nutr. Metab. Cardiovasc. Dis. 13:256-266.[Medline]
15. Dwyer, J. H., Allayee, H., Dwyer, K. M., Fan, J., Wu, H., Mar, R., Lusis, A. J. & Mehrabian, M. (2004) Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N. Engl. J. Med. 350:29-37.
16. Baylin, A., Kabagambe, E. K., Ascherio, A., Spiegelman, D. & Campos, H. (2003) Adipose tissue alpha-linolenic acid and nonfatal acute myocardial infarction in Costa Rica. Circulation 107:1586-1591.[Medline]
17. Campos, H. & Siles, X. (2000) Siesta and the risk of coronary heart disease: results from a population-based, case-control study in Costa Rica. Int. J. Epidemiol. 29:429-437.
18. Tunstall-Pedoe, H., Kuulasmaa, K., Amouyel, P., Arveiler, D., Rajakangas, A. M. & Pajak, A. (1994) Myocardial infarction and coronary deaths in the World Health Organization MONICA project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 90:583-612.[Medline]
19. Baylin, A., Kabagambe, E. K., Siles, X. & Campos, H. (2002) Adipose tissue biomarkers of fatty acid intake. Am. J. Clin. Nutr. 76:750-757.
20. Seidelin, K. N. (1995) Fatty acid composition of adipose tissue in humans. Implications for the dietary fat-serum cholesterol-CHD issue. Prog. Lipid Res. 34:199-217.[Medline]
21. Kabagambe, E. K., Baylin, A., Allan, D. A., Siles, X., Spiegelman, D. & Campos, H. (2001) Application of the method of triads to evaluate the performance of food frequency questionnaires and biomarkers as indicators of long-term dietary intake. Am. J. Epidemiol. 154:1126-1135.
22. Baylin, A., Kabagambe, E. K., Ascherio, A., Spiegelman, D. & Campos, H. (2003) High 18:2 trans-fatty acids in adipose tissue are associated with increased risk of nonfatal acute myocardial infarction in Costa Rican adults. J. Nutr. 133:1186-1191.
23. Kabagambe, E. K., Baylin, A., Siles, X. & Campos, H. (2003) Individual saturated fatty acids and nonfatal acute myocardial infarction in Costa Rica. Eur. J. Clin. Nutr. 57:1447-1457.[Medline]
24. Wood, D. A., Riemersma, R. A., Butler, S., Thomson, M., Macintyre, C., Elton, R. A. & Oliver, M. F. (1987) Linoleic and eicosapentaenoic acids in adipose tissue and platelets and risk of coronary heart disease. Lancet 1:177-183.[Medline]
25. Kardinaal, A. F., Aro, A., Kark, J. D., Riemersma, R. A., van ’t Veer, P., Gomez-Aracena, J., Kohlmeier, L., Ringstad, J., Martin, B. C. & Mazaev, V. P., et al (1995) Association between beta-carotene and acute myocardial infarction depends on polyunsaturated fatty acid status. The EURAMIC Study. European Study on Antioxidants, Myocardial Infarction, and Cancer of the Breast. Arterioscler. Thromb. Vasc. Biol. 15:726-732.
26. Pedersen, J. I., Ringstad, J., Almendingen, K., Haugen, T. S., Stensvold, I. & Thelle, D. S. (2000) Adipose tissue fatty acids and risk of myocardial infarction–a case-control study. Eur. J. Clin. Nutr. 54:618-625.[Medline]
27. Miettinen, T. A., Naukkarinen, V., Huttunen, J. K., Mattila, S. & Kumlin, T. (1982) Fatty-acid composition of serum lipids predicts myocardial infarction. Br. Med. J. 285:993-996.
28. Lemaitre, R. N., King, I. B., Raghunathan, T. E., Pearce, R. M., Weinmann, S., Knopp, R. H., Copass, M. K., Cobb, L. A. & Siscovick, D. S. (2002) Cell membrane trans-fatty acids and the risk of primary cardiac arrest. Circulation 105:697-701.
29. Borkman, M., Storlien, L. H., Pan, D. A., Jenkins, A. B., Chisholm, D. J. & Campbell, L. V. (1993) The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. N. Engl. J. Med. 328:238-244.
30. Phinney, S. D. (1996) Arachidonic acid maldistribution in obesity. Lipids 31(suppl.):S271-S274.
31. Phinney, S. D., Tang, A. B., Thurmond, D. C., Nakamura, M. T. & Stern, J. S. (1993) Abnormal polyunsaturated lipid metabolism in the obese Zucker rat, with partial metabolic correction by gamma-linolenic acid administration. Metabolism 42:1127-1140.[Medline]
32. Decsi, T., Csabi, G., Torok, K., Erhardt, E., Minda, H., Burus, I., Molnar, S. & Molnar, D. (2000) Polyunsaturated fatty acids in plasma lipids of obese children with and without metabolic cardiovascular syndrome. Lipids 35:1179-1184.[Medline]
33. Garaulet, M., Perez-Llamas, F., Perez-Ayala, M., Martinez, P., de Medina, F. S., Tebar, F. J. & Zamora, S. (2001) Site-specific differences in the fatty acid composition of abdominal adipose tissue in an obese population from a Mediterranean area: relation with dietary fatty acids, plasma lipid profile, serum insulin, and central obesity. Am. J. Clin. Nutr. 74:585-591.
34. Auwerx, J. (1999) PPARgamma, the ultimate thrifty gene. Diabetologia 42:1033-1049.[Medline]
35. Massiera, F., Saint-Marc, P., Seydoux, J., Murata, T., Kobayashi, T., Narumiya, S., Guesnet, P., Amri, E. Z., Negrel, R. & Ailhaud, G. (2003) Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern?. J. Lipid Res. 44:271-279.
This article has been cited by other articles:
|
|
 |
|
  A. Baylin, E. Ruiz-Narvaez, P. Kraft, and H. Campos {alpha}-Linolenic acid, {Delta}6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction Am. J. Clinical Nutrition, February 1, 2007; 85(2): 554 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Tuncman, E. Erbay, X. Hom, I. De Vivo, H. Campos, E. B. Rimm, and G. S. Hotamisligil A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease PNAS, May 2, 2006; 103(18): 6970 - 6975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Sacks and H. Campos Polyunsaturated Fatty Acids, Inflammation, and Cardiovascular Disease: Time to Widen Our View of the Mechanisms J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 398 - 400. [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Hjelte and A. Nilsson Arachidonic Acid and Ischemic Heart Disease J. Nutr., September 1, 2005; 135(9): 2271 - 2273. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Baylin, M. K. Kim, A. Donovan-Palmer, X. Siles, L. Dougherty, P. Tocco, and H. Campos Fasting Whole Blood as a Biomarker of Essential Fatty Acid Intake in Epidemiologic Studies: Comparison with Adipose Tissue and Plasma Am. J. Epidemiol., August 15, 2005; 162(4): 373 - 381. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
